This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our focus of research, the Werner protein, is one of disease-associated RecQ helicases. Its deficiency results in the Werner syndrome (WS), characterized by accelerated rate of mutation and the organism's inability to resolve a variety of genome-damaging events. Mutations in the WRN gene (also referred to as RECQ3 or RECQL2) don't appear to increase a person's susceptibility to DNA damage, and they alone do not cause the development of the disease. Instead they accelerate and exacerbate the disease that could develop even without this sensitizing mutation due to the damaging environmental agents. An important consequence of understanding the mechanism of a pathology is the ability to treat it more effectively, and even to prevent it in some cases. Aging research is extremely important considering the changing demographics worldwide, increased overall longevity and rise in elderly population. Understanding of the mechanisms that underlie aging and development of age-related disease due to genomic aberration can lead us to improved treatment and alleviated burden of age-related disease. Activity of proteins such as WRN suggests that the complex process of ageing is controlled by a conserved number of genes. However, mutations in a series of proteins do not suggest that their normal function is involved in promoting longevity. We are interested in understanding how normal function of this protein stalls senescence. In order to determine these mechanisms we study protein function in normal and diseased states with the use of proteomics. Resources that are currently available to us include modern analytical instrumentation, support from computational sciences, and access to rare biological samples. Our work is aimed at defining consistently associated proteins and post-translational modifications of WRN that are required or are causal for its function in human cells. This knowledge will increase our understanding of WS pathogenesis and provide insight into novel strategies to alter the progression of WS or associated diseases such as ASCVD, cancer, diabetes, and osteoporosis.